Anti-aggregatory peptides

This invention relates to compounds which are effective for inhibiting platelet aggregation, pharmaceutical compositions for effecting such activity, a method for inhibiting platelet aggregation and clot formation in a mammal, and a method for inhibiting reocclusion of a blood vessel following fibrinolytic therapy.

Skip to:  ·  Claims  ·  References Cited  · Patent History  ·  Patent History

Claims

1. A compound of formula (II): ##STR4## (II) wherein: A' is a D- or L-amino acid chosen from Arg, HArg, (Me.sub.2)Arg, (Et.sub.2)Arg, Ala, Gly, His, Abu, Lys or an.alpha.-R' substituted derivative thereof, or Pro;

B' is an.alpha.-R' substituted derivative of D- or L-Arg;
C' is a D or L amino acid chosen from Tyr, (Alk)Tyr, Phe, (4'W)Phe, HPhe, Phg, Trp, His, Ser, (Alk)Ser, Thr, (Alk)Thr, (Alk)Cys, (Alk)Pen, Ala, Val, Nva, Met, Leu, lie, Nle or Nal, or an.alpha.-R' substituted derivative thereof;
W is halogen or Alk;
Y is NR.sub.1 R.sub.2 or OR.sub.3;
R.sub.1 and R.sub.2 are each independently H, Alk or (CH.sub.2).sub.p Ph;
R.sub.3 is Alk, (CH.sub.2).sub.p Ph or H;
X is R.sub.4 R.sub.5 N or H;
R.sub.4 is H or Alk;
R.sub.5 is H, Alk, HCO, AlkCO, PhCH.sub.2 or Ph(CH.sub.2).sub.q CO;
R' is Alk or PhCH.sub.2;
Z.sub.1 is a D- or L-isomer of Cys, Pen or APmp;
Z.sub.2 is a D- or L- isomer of Cys, Pen or APmp;
q, m and n are independently 0 or 1; and
p is 0, 1, 2or 3;

2. A compound according to claim 1 which is:

N.sup..alpha. -Ac-Cyclo(S,S)Cys-MeArg-Gly-Asp-Ser-Cys-NH.sub.2;
N.sup..alpha. -Ac-Cyclo(S,S)Cys-MeArg-Gly-Asp-Ser-Pen-NH.sub.2;
N.sup..alpha. -Ac-Cyclo(S,S)Cys-MeArg-Gly-Asp-(Me)Ser-Cys-NH.sub.2;
Cyclo(S,S)Mpr-MeArg-Gly-Asp-Ser-Cys-NH.sub.2;
N.sup..alpha. -Ac-Cyclo(S,S)Cys-MeArg-Gly-Asp-Cys-NH.sub.2;
Cyclo(S,S)Mpr-MeArg-Gly-Asp-Pen-NH.sub.2;
N.sup..alpha. -Ac-Cyclo(S,S)Cys-MeArg-Gly-Asp-Pen-NH.sub.2;
N.sup..alpha. -Ac-Cyclo(S,S)Cys-MeArg-Gly-Asp-Tyr-Cys-NH.sub.2;
N.sup..alpha. -Ac-Cyclo(S,S)Pen-MeArg-Gly-Asp-Pen-NH.sub.2;
N.sup..alpha. -Ac-Cyclo(S,S)Cys-D-MeArg-Gly-Asp-Pen-NH.sub.2.

3. A method for inhibiting platelet aggregation in a mammal comprising administering an effective amount of a peptide according to claim 1, and a pharmaceutically acceptable carrier.

4. A method for inhibiting clot formation in a mammal comprising administering an effective amount of a peptide according to claim 1, and a pharmaceutically acceptable carrier.

5. A method for preventing or treating myocardial infarction in a mammal comprising administering an effective amount of a peptide according to claim 1, and a pharmaceutically acceptable carrier.

6. A method for preventing or treating stroke in a mammal comprising administering an effective amount of a peptide according to claim 1, and a pharmaceutically acceptable carrier.

7. A compound according to claim 1, in which B' is an.alpha.-R' substituted derivative of Arg.

8. A compound according to claim 1 in which m is 1 and n is 0.

9. A compound according to claim 8 in which B' is MeArg.

10. A compound according to claim 8 in which A' is Gly or Arg.

11. A compound according to claim 1 in which m is 0 and n is 1.

12. A compound according to claim 11 in which C' is Ser, (Me)Ser, Thr, Tyr, Phe, or Nal.

13. A compound according to claim 11 in which B' is MeArg.

14. A compound according to claim 1 in which both m and n are 0 and B' is MeArg.

15. The compound according to claim 2 which is N.sup..alpha. -Ac-Cyclo(S,S)Cys-MeArg-Gly-Asp-Ser-Cys-NH.sub.2.

16. The compound according to claim 2 which is N.sup..alpha. -Ac-Cyclo(S,S)Cys-MeArg-Gly-Asp-Cys-NH.sub.2.

17. The compound according to claim 2 which is N.sup..alpha. -Ac-Cyclo(S,S)Cys-MeArg-Gly-Asp-Pen-NH.sub.2.

18. The compound according to claim 2 which is N.sup..alpha. -Ac-Cyclo(S,S)Cys-MeArg-Gly-Asp-Tyr-Cys-NH.sub.2.

19. A pharmaceutical composition for inhibiting platelet aggregation in a mammal, which comprises an effective amount therefor of a peptide according to claim 1 and a pharmaceutically acceptable carrier.

20. A pharmaceutical composition for inhibiting platelet aggregation in a mammal, which comprises an effective amount therefor of a peptide according to claim 2 and a pharmaceutically acceptable carrier.

21. A pharmaceutical composition for inhibiting platelet aggregation in a mammal, which comprises an effective amount therefor of a peptide according to claim 17 and a pharmaceutically acceptable carrier.

22. A pharmaceutical composition for inhibiting platelet aggregation in a mammal, which comprises an effective amount therefor of a peptide according to claim 17 and a pharmaceutically acceptable carrier.

Referenced Cited
U.S. Patent Documents
4397842 August 9, 1983 Goldstein et al.
4517686 May 21, 1985 Ruoslahti et al.
4544500 October 1, 1985 Bittle et al.
4578079 March 25, 1986 Ruoslahti et al.
4589881 May 20, 1986 Pierschbacher et al.
4614517 September 30, 1986 Ruoslahti et al.
4661111 April 28, 1987 Ruoslahti et al.
4683291 July 28, 1987 Zimmerman et al.
4857508 August 15, 1989 Adams et al.
Foreign Patent Documents
204480 December 1986 EPX
265129 April 1988 EPX
275748 July 1988 EPX
WO8400540 February 1984 WOX
WO8803151 May 1988 WOX
WO8905150 June 1989 WOX
Other references
  • D'Souza et al., J. Biol. Chem., 263, 3943 (1988). Pierschbacher et al., J. Biol. Chem., 262, 17294 (1987). Plow et al., Blood, 70, 110 (1987). Ruggeri et al., Proc. Natl. Acad. Sci., 83, 5708 (1986). Ginsberg et al., J. Biol. Chem., 260, 3931 (1985). Plow et al., Proc. Natl. Acad. Sci., 82, 8057 (1985). Haverstick et al., Blood, 66, 946 (1985). Pierschbacher et al., Proc. Natl. Acad. Sci., 81, 5985 (1984). Pierschbacher et al., Nature, 309, 30 (1984). Yasuda et al., Clin. Res., 34, 2, 634A (1986). Coller et al., Blood, 66, 1456 (1985). Ohlstein et al., Thrombosis Research, 46, 575 (1987). Aiken et al., Prostaglandins, 19, 629 (1980). Ruoslahti et al., Science, 238, 491 (1987). Nievelstein et al., Thromb. and Hemostasis, 58, 213 (1987).
Patent History
Patent number: 5849690
Type: Grant
Filed: Jul 22, 1992
Date of Patent: Dec 15, 1998
Assignee: SmithKline Beecham Corporation (Philadelphia, PA)
Inventors: Fadia El-Fehail Ali (Cherry Hill, NJ), James Samanen (Phoenixville, PA)
Primary Examiner: Cecilia J. Tsang
Assistant Examiner: Patrick R. Delaney
Attorneys: Charles M. Kinzig, Edward T. Lentz
Application Number: 7/918,487
Classifications
Current U.S. Class: 514/9; 514/11
International Classification: C07K 400;